Chronic exposure to manganese (Mn) causes neurotoxicity, referred to as manganism, with common clinical features of parkinsonism. 17β-estradiol (E2) and tamoxifen (TX), a selective estrogen receptor modulator (SERM), afford neuroprotection in several neurological disorders, including Parkinson’s disease (PD). In the present study, we tested if E2 and TX attenuate Mn-induced neurotoxicity in mice, assessing motor deficit and dopaminergic neurodegeneration. We implanted E2 and TX pellets in the back of the neck of ovariectomized C57BL/6 mice two weeks prior to a single injection of Mn into the striatum. One week later, we assessed locomotor activity and molecular mechanisms by immunohistochemistry, real-time quantitative PCR, western blot and enzymatic biochemical analyses. The results showed that both E2 and TX attenuated Mn-induced motor deficits and reversed the Mn-induced loss of dopaminergic neurons in the substantia nigra. At the molecular level, E2 and TX reversed the Mn-induced decrease of (1) glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) mRNA and protein levels; (2) transforming growth factor-α (TGF-α) and estrogen receptor-α (ER-α) protein levels; and (3) catalase (CAT) activity and glutathione (GSH) levels, and Mn-increased (1) malondialdehyde (MDA) levels and (2) the Bax/Bcl-2 ratio. These results indicate that E2 and TX afford protection against Mn-induced neurotoxicity by reversing Mn-reduced GLT1/GLAST as well as Mn-induced oxidative stress. Our findings may offer estrogenic agents as potential candidates for the development of therapeutics to treat Mn-induced neurotoxicity.

长期暴露于锰（Mn）会引起神经毒性，称为锰症，具有帕金森氏症的常见临床特征。17β-雌二醇（E2）和他莫昔芬（TX）是一种选择性雌激素受体调节剂（SERM），可在包括帕金森氏病（PD）在内的多种神经系统疾病中提供神经保护作用。在本研究中，我们测试了E2和TX是否能减轻Mn诱导的小鼠神经毒性，从而评估运动功能障碍和多巴胺能神经变性。在将Mn单次注射到纹状体之前两周，我们将E2和TX团块植入卵巢切除的C57BL / 6小鼠的脖子后方。一周后，我们通过免疫组织化学，实时定量PCR，蛋白质印迹和酶促生化分析评估了运动活性和分子机制。结果表明，E2和TX均减弱了黑质中Mn引起的运动功能障碍，并逆转了Mn引起的多巴胺能神经元损失。在分子水平上，E2和TX逆转了Mn诱导的（1）谷氨酸天冬氨酸转运蛋白（GLAST）和谷氨酸转运蛋白1（GLT-1）mRNA和蛋白质水平的降低；（2）转化生长因子-α（TGF-α）和雌激素受体-α（ER-α）蛋白水平；（3）过氧化氢酶（CAT）活性和谷胱甘肽（GSH）水平，以及锰增加（1）丙二醛（MDA）水平和（2）Bax / Bcl-2比。这些结果表明，E2和TX通过逆转Mn降低的GLT1 / GLAST以及Mn诱导的氧化应激而提供针对Mn诱导的神经毒性的保护。